Clinical relevance of double heterozygosity revealed by next-generation sequencing of homologous recombination repair pathway genes in South African breast cancer patients

• DOI: 10.1007/s10549-024-07362-2
• Publication Date: 2024-05-30T04:06:12Z
• Authors: Nerina C. van der...; Ines Buccimazza; Bianca Rossouw; Monica Araujo; Kholiwe S. Ntaita; Mardelle Schoeman; Karin Vorster; Kgabo Napo; Maritha J. Kotze; Jaco Oosthuizen
• Keywords: Clinical Significance

Abstract Purpose Genetically predisposed breast cancer (BC) patients represent a minor but clinically meaningful subgroup of the disease, with 25% all cases associated actionable variants in BRCA1/2 . Diagnostic implementation next-generation sequencing (NGS) resulted rare identification BC double heterozygosity for deleterious genes partaking homologous recombination repair DNA. As clinical heterogeneity poses challenges genetic counseling, this study focused on occurrence and relevance heterozygous South Africa. Methods DNA samples were diagnostically screened using NGS-based Oncomine™ BRCA Expanded Research Assay. Data was generated Ion GeneStudio S5 system analyzed Torrent Suite™ reporter software. The significance detected determined international variant classification guidelines treatment implications. Results Six 1600 (0.375%) tested identified as being bi-allelic two germline likely pathogenic or variants. Most present , including founder-related small deletions three cases, family-specific ATM, BARD1, FANCD2, NBN, TP53 scientific interpretation based tumor characteristics each case. Conclusion This increased current knowledge risk implications co-occurrence more than one susceptibility genes, confirmed to be condition Further molecular pathology-based studies are warranted determine whether decision-making is affected by detection second carriers.